Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome.

Importance: There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS). Objective: To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate. Design, Setting, and Participants: This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms. Main Outcomes and Measures: Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model. Results: Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02). Conclusions and Relevance: Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.

OBJECTIVE: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. METHODS: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays. RESULTS: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group. INTERPRETATION: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS.

Levels of serum and cerebrospinal fluid soluble CD27 in the diagnosis of leptomeningeal involvement of hematolymphoid malignancies.

Reportedly, soluble CD27 (sCD27) is a sensitive and specific marker for leptomeningeal involvement (LI) of CD27-expressing lymphoproliferations, such as B-cell non-Hodgkin's lymphoma and chronic B-lymphocytic leukemia. On morphologic analysis of cerebrospinal fluid (CSF), one third of patients suspected of LI have false negatives, so a diagnostic marker for LI in B-cell non-Hodgkin's lymphoma or B-lymphocytic leukemia would be extremely valuable. sCD27 was detected in the serum and CSF samples from 35 selected patients in whom 18 cases of acute lymphoblastic leukemia (ALL) (3 with LI), 7 of non-Hodgkin's lymphoma, and 5 of acute myelogenous leukemia (3 with LI) were submitted for (immuno)morphologic detection of malignant cells and intrathecal therapy, along with samples from 5 control patients (2 submitted for epidural hemorrhage, 3 for lumbar disc protrusion). Concentrations of CSF-sCD27 were determined by enzyme-linked immunosorbent assay (PeliKine Compact Human Soluble CD27 ELISA Kit, Cat. No. M1960; Research Diagnostics Inc., Concord, Mass). The cutoff value was 350 U/mL. Serum and CSF-sCD27 concentrations above the cutoff value were not detected. Although it is unlikely that LI would be present in patients with chronic lymphoproliferation who have normal sCD27 concentrations in CSF samples, the determination of CSF-sCD27 is not sufficiently specific to allow it to serve as a reliable tumor marker.

Cerebrospinal fluid soluble CD27 levels in children with non-Hodgkin lymphomas.

The authors investigated the diagnostic value of cerebrospinal fluid (CSF) soluble CD27 (sCD27) for leptomeningeal involvement of non-Hodgkin lymphomas (NHL). Cytospin slides were prepared from CSF samples of 64 children treated for NHL. sCD27 levels were determined by sandwich ELISA method using two CD27 monoclonal antibodies. 8/194 (4.1%) samples were considered tumor-positive by cytology. Mean sCD27 values were 5.8 and 13.8 U/mL in tumor-negative and tumor-positive samples, respectively (p =.18). 26/194 samples were false positive and 2/194 false negative (cutoff: 7 U/mL) (sensitivity, 75 %; specificity, 86%; positive predictive value, 18.8%; negative predictive value, 98.8%; accuracy, 85.6%). With these results, the value of adding sCD27 determination to the cytological CSF examination remains questionable.

Increased levels of soluble CD27 in the cerebrospinal fluid are not diagnostic for leptomeningeal involvement by lymphoid malignancies.

Soluble CD27 (sCD27) reportedly is a sensitive and specific marker for leptomeningeal involvement (LI) of CD27-expressing lymphoproliferations such as B-cell non-Hodgkin's lymphoma (B-NHL) or chronic B-lymphocytic leukemia (B-CLL). Because morphological analysis of cerebrospinal fluid (CSF) in patients suspected of LI is false negative in one-third of patients, a diagnostic marker for LI by B-NHL or B-CLL would be very valuable. sCD27 was determined in the first CSF sample from each of 102 unselected patients submitted for (immuno)morphologic detection of malignant cells. The patients were considered to have LI if either (immuno)morphologic analyses showed tumor cells or if neuroradiological evaluation showed typical abnormalities consistent with LI. Patients were suspected of having LI if CSF samples revealed atypical lymphocytes and/or if clinical symptoms and signs suggestive of LI were present, but clinical follow-up was shorter than 3 months because of deterioration of the patient. LI was considered absent if (immuno)morphologic analyses of CSF samples were negative without evidence for LI during 3 months of clinical follow-up. In patients with chronic lymphoproliferative disorders [mainly B-non-Hodgkin's lymphoma (NHL)], sCD27 concentrations were significantly higher in the CSF samples of 16 patients with confirmed or suspected LI than in those of 46 patients without LI. However, sCD27 was also increased in a variety of other predominantly inflammatory neurological disorders including herpes simplex and zoster infections. The positive predictive value of sCD27 determination for LI was only 54%, but the negative predictive value was 92%. Normal sCD27 concentrations in CSF samples of patients with chronic lymphoproliferation makes LI unlikely, but the determination of CSF sCD27 is not sufficiently specific to serve as a reliable tumor marker.

Diagnostic utility of CSF soluble CD27 for primary central nervous system lymphoma in immunocompetent patients.

The aim of this study is to determine the diagnostic utility of cerebrospinal fluid (CSF) soluble CD27 (sCD27) as a tumor marker for primary central nervous system lymphoma (PCNSL) in immunocompetent patients. A total of 93 CSF samples were collected from the following four patient groups: the PCNSL group, 13 patients (26 samples) with PCNSL, 12 samples obtained at initial diagnosis, 10 during therapy, four at complete remission; the other brain tumors (OBT) group, 30 patients (30 samples) with other brain tumors; the other neurological diseases (OND) group, 25 (25 samples) with other neurological diseases; the inflammatory neurological diseases (IND) group, 12 patients (12 samples) with inflammatory neurological diseases. sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value was found to be 15 U ml-1. The CSF sCD27 levels were over 15 U ml-1 in 23 of the 26 PCNSL samples and were significantly higher than those in the OBT and OND groups in which all samples were below 15 U ml-1. Elevated CSF sCD27 levels were also observed in 11 of 12 IND samples. In the two PCNSL patients whose CSF sCD27 levels were studied longitudinally, the sCD27 levels correlated very well with remission and relapse of the disease. CSF sCD27 is useful as a tumor marker for PCNSL in immunocompetent patients, and is also useful to evaluate the effect of various types of treatment. Although there was a large cross-reactivity in the CSF sCD27 levels between PCNSL and IND group, white blood cell count in the CSF is helpful to distinguish these two diseases.

Cerebrospinal fluid concentrations of soluble CD27 in HTLV-I associated myelopathy and multiple sclerosis.

OBJECTIVES: Stimulation of T lymphocytes via the T cell receptor strongly enhances CD27 membrane expression and induces the release of a soluble 32 kDa form of CD27 (sCD27). CD27 is a member of the TNF receptor family, a group of molecules that have important roles in lymphocyte differentiation and survival. Raised concentrations of sCD27 have been reported in various immunopathological conditions and there is evidence that this molecule can serve as a marker of T cell activation in vivo. Concentrations of sCD27 in CSF were compared between patients with T cell mediated neurological disease and non-inflammatory controls. Also, the relation of CSF-sCD27 concentrations with clinical disease activity was investigated in patients with multiple sclerosis. METHODS: Four groups were studied: (1) eight patients with HTLV-1 associated myelopathy/ tropical spastic paraparisis (HAM)/TSP), (2) eight HTLV-I carriers, (3) 41 patients with multiple sclerosis, and (4) 43 patients with other neurological disease (OND). Concentrations of CSF-sCD27 were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Quantification of CSF-sCD27 differentiates patients with HAM/TSP from HTLV-I carriers (p<0.01) and from patients with OND (p<0.001). Moreover, the multiple sclerosis patient group was different from the OND group (p<0.0001). In patients with multiple sclerosis, CSF-sCD27 concentrations were higher in 24 patients with clinically active disease than in 17 with clinically stable disease. In addition, most of the patients with multiple sclerosis with high sCD27 concentrations showed an increase in EDSS, whereas none of the patients with low sCD27 had an EDSS increase. CONCLUSIONS: As a reliable marker of immunological disease activity in inflammatory white matter disease is still not available, it is proposed that quantification of CSF-sCD27 concentrations is a good candidate. Also, it may serve as a tool to stratify neurological diseases in inflammatory and non-inflammatory states.

Increased levels of CSF soluble CD27 in patients with primary central nervous system lymphoma.

The aim of this study is to determine the diagnostic value of cerebrospinal fluid (CSF) soluble CD27 (sCD27) as a tumor marker for primary central nervous system lymphoma (PCNSL). We examined sCD27 levels in CSF obtained from various types of brain tumor patients. Forty-two patients were studied (including 12 PCNSL patients) who had not received any therapy for their tumors. In all PCNSL cases, CSF sCD27 levels were more than 15 U/ml (median 84.5 U/ml, range 17-484 U/ml) and in other brain tumor cases, CSF sCD27 levels were all less than 15 U/ml. Our data suggest that CSF sCD27 levels are useful to distinguish PCNSL from other brain tumors.

Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies.

Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.

Low levels of specific T cell activation marker CD27 accompanied by elevated levels of markers for non-specific immune activation in the cerebrospinal fluid of patients with AIDS dementia complex.

Concentrations of soluble receptors for tumor necrosis factor (sTNFR-p55 and sTNFR-p75) and soluble T cell antigens CD25 and CD27 (sCD25 and sCD27) were measured in paired serum/cerebrospinal fluid (CSF) samples of 15 patients with AIDS dementia complex (ADC) and 15 HIV-infected control subjects (11 with other central nervous system (CNS) infections and four without CNS infection). In this study levels of sTNFR-p55, sTNFR-p75 and sCD25 were elevated in the CSF of ADC patients and of the 11 patients with other CNS infections, whereas CSF-levels of the specific T cell marker sCD27 were lower in patients with ADC as compared to the control subjects with and without other CNS infections. This pattern suggests a relative failure of eliciting a T cell-mediated immune response intrathecally in patients with ADC.